A group (n=29) of HIV-infected individuals termed long-term non-progressors (LTNPs) whose disease has not progressed over periods from 7 to 18 years were studied. Levels of viral burden and replication were quite low in peripheral blood (PB) and lymph node (LN) mononuclear cells (MC) of LTNPs compared to progressors. Lymph node MC from LTNPs exhibit incomplete expression of rev/nef HIV mRNAs, possibly due to mutations within key HIV splice acceptor sites. Of interest was the fact that relatively high levels of plasma viremia were noted in the majority of LTNPs. The degree of follicular hyperplasia and the total nodal and germinal center areas were significantly lower in LTNPs. In contrast to progressors, the lymph node architecture of the LTNPs was preserved despite many years of infection. Variable degrees of virus trapping were detected in lymph node germinal centers; several patients had little trapping of extracellular virions. Virus particles were virtually never detected in tissue or cell suspensions by electron microscopy, and only rarely were HIV-expressing cells detected by in situ hybridization. These data together with studies of lymphoid tissue in progressors suggests that disease progression is at least in part related to the deposition of virions on the follicular dendritic cell network of LN germinal centers, persistent activation of the LN microenvironment, active virus replication, and progressive destruction of lymphoid tissue. From an immunological standpoint, HIV-specific cytotoxicity against gag proteins was consistently observed in PBMC of LTNPs. Proliferative responses to a variety of stimuli were preserved in PBMC of LTNPs. Although sera from LTNPs had higher titers of neutralizing antibodies to laboratory and primary HIV isolates, viruses isolated from LTNPs were resistant to neutralization by autologous serum. In addition, viruses from LTNPs showed little evidence for heightened sensitivity to neutralization by heterologous sera. CD4+ T cells from LTNPs as well as nearly all patients tested with progressive disease were able to respond ex vivo to interleukin-2 by normal activation of the Jak/STAT signalling pathway. Intensive study of LTNPs should shed valuable insight into the pathogenic mechanisms of HIV disease and hopefully will provide important information for the development of therapeutic and vaccine strategies.